EHHADH – primary Fanconi syndrome

EHHADH encodes the peroxisomal L-bifunctional enzyme enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase, which participates in peroxisomal β-oxidation of fatty acids. Heterozygous mutations in EHHADH have been implicated in an autosomal dominant form of primary Fanconi syndrome, characterized by generalized proximal tubule dysfunction and renal losses of electrolytes and low-molecular-weight nutrients.

A heterozygous missense variant c.7G>A (p.Glu3Lys) has been identified in a 5-generation family[PMID:24401050]. This variant segregated with disease in 8 affected relatives[PMID:24401050], consistent with autosomal dominant inheritance.

Affected individuals exhibit hyperphosphaturia, glycosuria, aminoaciduria, proximal renal tubular acidosis, and low-molecular-weight proteinuria[PMID:25492894]. Despite profound tubular dysfunction, glomerular filtration remains preserved, distinguishing isolated primary Fanconi syndrome from systemic tubular disorders.

Mechanistic studies in patient-derived cells and tissue demonstrate that the p.Glu3Lys mutation creates a cryptic mitochondrial targeting motif, leading to mistargeting of EHHADH to mitochondria and impaired oxidative phosphorylation in proximal tubule cells[PMID:24401050]. This mislocalization disrupts mitochondrial supercomplex formation and reduces ATP generation required for active solute transport.

Further functional work shows that mutant EHHADH integrates into the mitochondrial trifunctional protein complex, causing β-oxidation defects and accumulation of acylcarnitines. Secondary reductions in Na+/K+-ATPase activity decrease reabsorptive capacity, recapitulating the Fanconi phenotype in cellular models[PMID:27160910].

Collectively, the genetic segregation and concordant functional assays support a pathogenic dominant-negative mechanism for EHHADH in primary Fanconi syndrome. This evidence underpins clinical genetic testing for EHHADH variants in unexplained proximal tubulopathies and highlights mitochondrial targeting as a potential therapeutic focus.

References

• The New England journal of medicine • 2014 • Mistargeting of peroxisomal EHHADH and inherited renal Fanconi's syndrome. PMID:24401050
• Cell reports • 2016 • Renal Fanconi Syndrome Is Caused by a Mistargeting-Based Mitochondriopathy. PMID:27160910
• Nephrology, dialysis, transplantation • 2015 • Renal Fanconi syndrome: taking a proximal look at the nephron. PMID:25492894

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